The present invention relates to new compounds which have a cooling effect on the skin or mucous membranes, notably the buccal mucosae. More particularly, the application deals with compounds of the formula 
in which R=H and n is a whole number from 1 to 4 or R=CH3 and n is a whole number from 0 to 4, as well as the use of the said compounds as cooling agents.
The prior art describes a large number of compounds of natural or synthetic origin, which have been observed to have a cooling effect on human skin or mucosae, the most well-known compound being (xe2x88x92)-menthol, which is found naturally in oil of mint, notably of mentha arvensis L and mentha viridis L.
Among the large number of publications in the field of synthetic cooling agents, particularly those derived from menthol, we should cite application DE-OS-2608226, which describes certain esters of menthol with hydroxylated carboxylic acids, for example glycolic acid, xcex2-hydroxybutyric acid or xcex1-hydroxycaprylic acid, but in particular the ester of lactic acid. Application EP-A-507190 describes cooling agents which are acetals of certain ketones, in particular 1-menthone glycerol ketal.
Application EP-A-583651 discloses another group of cooling agents derived from menthol, that is, asymmetric menthol carbonates, carbamates and thiocarbamates, in particular menthol ethylene glycol carbonate and menthol propane-1,2-diol carbonate.
In order to be suitable as a cooling agent, a compound must fulfill certain requirements. Firstly, the compound must not have an irritant effect on the skin or in particular the mucosae, which would prevent its use in certain applications, for example those in which the said compound is used in large quantities and/or the application product may come into contact with certain sensitive parts of the mucosae. For the reasons given above, the use of menthol is limited, as is the case also of other compounds which prove unsuitable for use in certain products.
Furthermore, for many applications it is desirable that the cooling effect be of prolonged duration, in order that this effect can still be perceived several minutes after the active agent is no longer in contact with the skin or mucosae. As menthol is highly volatile, it does not fulfill this condition in spite of its pronounced cooling effect.
In the majority of applications it is also desirable to have cooling agents which do not have a strong odour, as is the case of menthol which has the typical and pronounced odour of peppermint.
Finally, a cooling agent must not have an unpleasant taste, so that applications in the flavourings industry are possible. Once again, menthol has a marked bitter taste when used in high concentrations.
To summarise, it may be said that although menthol in particular, but also the other above-mentioned compounds which have a cooling effect, fulfill some of the above-mentioned conditions required of cooling substances (xe2x80x9ccooling agentsxe2x80x9d), scientists are still searching for new compounds with properties which enable novel and preferably advantageous effects to be obtained in this field.
We have now synthesised a new class of compounds of general formula: 
in which R=H and n is a whole number from 1 to 4, or R=CH3and n is a whole number from 0 to 4.
We have been able to establish that this class of compounds has all the desirable properties of a cooling agent, i.e.:
they are non-irritant compounds
the cooling effect is pronounced and long-lasting
the compounds do not have a strong odour
the taste of the compounds is neutral, thus being able to reinforce the typical taste of the ingredients in flavour applications.
The class of compounds of formula (I) does not have the typical taste of menthol, but a more neutral taste which can vary according to the length of the chain linked to the carboxylic function, the nature of the terminal substituent on the said chain (H or CH3), or the isomeric configuration of the menthol used as the starting substance for the preparation of the formula (I) compounds. In fact, the stereoisomery of compounds (I) is dictated by that of the starting menthol, and one can thus obtain all the stereoisomers of the compounds (I) corresponding to those of menthol. Of these stereoisomers, the formula (I) compounds derived from (xe2x88x92)-menthol are especially advantageous and preferred according to the invention for their marked cooling effect when used in the applications described below.
As formula (I) shows, the compounds according to the invention may have an alcohol or methoxy group in the terminal position of the chain. In the context of the present invention the use of compounds having a methoxy group in the terminal position is preferred.
Of the said compounds, the ones preferred are those which comply with formula (I) in which n=0 or 1, i.e. (xe2x88x92)-menthyl methoxyacetate, or (1R,2S,5R)-3-menthyl methoxyacetate, and (xe2x88x92)-menthyl 3,6-dioxaheptanoate, or (1R,2S,5R)-3-menthyl 3,6-dioxaheptanoate. (xe2x88x92)-Menthyl methoxyacetate has a head note fruity taste resembling that of menthyl acetate, whereas (xe2x88x92)-menthyl 3,6-dioxaheptanoate has a bitter taste. These two compounds are highly advantageous in flavours and one or the other or even both of these compounds may be used, depending on the envisaged application. For example, in applications in which a bitter taste is undesirable, (xe2x88x92)-menthyl methoxyacetate will be preferred, while (xe2x88x92)-menthyl 3,6-dioxaheptanoate will be used in cases where the bitter taste is an advantage, for example in citrus-based edible products.
In accordance with another embodiment of the invention, a mixture of (xe2x88x92)-menthyl methoxyacetate and (xe2x88x92)-menthyl 3,6-dioxaheptanoate is used. In these mixtures, the two constituents may be present in highly variable relative proportions depending on the desired effect. In fact, the use of these mixtures enables certain gustatory characteristics of one or the other of these two compounds to be suppressed when they are less advantageous in certain applications, while reinforcing the refreshing effect. We have established that this synergistic effect between the two compounds was best manifested with mixtures containing the two compounds in similar quantities by weight, that is about 50% of each by weight; these mixtures are therefore preferred according to the invention.
However, given that each of the compounds is a useful cooling ingredient in itself, it is clear that the invention also relates to mixtures of the two compounds in which the proportion of each is varied from 0 to 100% by weight of the mixture.
Moreover, these two compounds also lend themselves to applications other than in the flavour industry, for example in body-care or cosmetic products.
Thus the compounds of the invention may be used in all fields in which a cooling effect is to be imparted to the products in which they are incorporated. By way of example one may cite beverages such as fruit juices, soft drinks or cold tea, ice creams and sorbets, sweets, confectioneries, chewing gum, chewing tobacco, cigarettes, pharmaceutical preparations, dental-care products such as dentifrice gels and pastes, mouth washes, gargles, body and hair care products such as shampoos, shower or bath gels, body deodorants and antiperspirants, after-shave lotions and balms, shaving foams, perfumes, etc.
The proportions in which the compounds of the invention may be incorporated into the various products mentioned above vary within a wide range of values. These values depend on the nature of the article or product to which a cooling effect is to be imparted and on the effect required, as well as on the nature of the co-ingredients in a given composition when the compounds-of the invention are used in a mixture with flavouring or perfuming co-ingredients, solvents or adjuvants commonly used in the art.
By way of example one may cite typical concentrations of the order of 0.001 to 5% or even more, preferably 0.002 to 1%, by weight of this compound relative to the cooling finished product in which it is incorporated.
It should be noted that the concentrations of the compounds of the invention used in these applications depend both on the product to be flavoured and on the desired effect. Thus for example in applications such as beverages and sweets, concentrations of the order of 0.005 to 0.1% will typically be used, whereas for flavouring dentifrices and chewing gums the compounds of the invention will typically be used in concentrations within the range 0.2-0.3 and 0.5-1%.
The syntheses used to obtain the products of formula (I) all use menthol as the starting substance. One of the possible syntheses consists in an esterification of the said menthol with acetic acid which is substituted at position xcex1, that is to say a compound of formula 
in which n and R have the meanings assigned in formula (I). The reaction takes place under the catalytic action of an acid, such as for example p-toluenesulphonic acid, phosphoric acid or any acid known for this type of esterification. The reaction is preferably performed in a solvent which permits separation of the water formed by azeotropic distillation, e.g. toluene, benzene or xylene.
Another synthesis involves, in the first stage, esterification of the menthol with xcex1-halogenated acetic acid, preferably 2-bromoacetic acid. This esterification is performed under conditions similar to those described in the preceding paragraph. The menthyl 2-halogenoacetate thus obtained is then converted into the desired product by a xe2x80x9cWilliamsonxe2x80x9d etherification reaction. In this reaction, an alcoholate of a compound of formula 
As the alcoholate one may use the alcoholate of an alkali metal, preferably sodium. An aprotic polar solvent such as, for example, dimethyl formamide, is preferably used for the Williamson reaction.
After the reaction, the formula (I) compounds are isolated and purified by conventional techniques, for example distillation or chromatography.
The invention will now be described in greater detail in the examples below, in which temperature is indicated in degrees Celsius and the abbreviations have the usual meaning in the art.